A program of pharmacogenetic investigation in drug metabolism, and toxicity of drugs and other environmental chemicals is proposed. The investigations will be performed in human families, in genetically defined experimental animal models, and subcellular systems of human and animal tissues. This is an interdisciplinary program combining investigators from pharmacology and human and mouse genetics with extensions into biological chemistry, toxicology and molecular biology. Specifically, the program will undertake 1) studies to determine the structural and functional nature of isozymic differences of rapid and slow acetylator N-acetyltransferases; 2) experimental and clinical studies to determine the significance and relationship of human serum esterases to organophosphate toxicity and drug metabolism; and 3) molecular biology (gene cloning) studies to determine whether the hereditary difference in the usual human serum cholinesterase and its isozymic variants are accounted for by DNA polymorphisms.